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CN1049334C - Fatty acid treatment - Google Patents

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Publication number
CN1049334C
CN1049334C CN93118320A CN93118320A CN1049334C CN 1049334 C CN1049334 C CN 1049334C CN 93118320 A CN93118320 A CN 93118320A CN 93118320 A CN93118320 A CN 93118320A CN 1049334 C CN1049334 C CN 1049334C
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acid
gla
calcium
dgla
medicine
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CN1091285A (en
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D·F·霍罗宾
B·E·雷诺兹
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Scotia Holdings PLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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  • Bioinformatics & Cheminformatics (AREA)
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  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Fats And Perfumes (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Abstract

Increasing gut calcium absorption in humans or animals by the administration of GLA, DGLA or LA as such or in salt or other pharmacologically acceptable form, optionally in association with EPA, DHA or other EFA in similar forms, specifically useful in the treatment of osteoporosis.

Description

The new purposes of fatty acid medicament
The present invention relates to the fatty acid medicament, particularly increase the absorption of intestinal, specifically relate to the treatment osteoporosis calcium.
The transduction pathway of main serial polyunsaturated fatty acid is shown in following table 1 in the body;
Table 1
Figure C9311832000031
Above-mentioned path generally is irreversible, and n-3 and the acid of n-6 series also can not be changed mutually in human body.
In fact, corresponding 18 carbonic acid of these acid system called afters of all-cis formula configuration, the derivant of 20 carbonic acid or behenic acid, as α-9,12-octadecadienoic acid or δ-4,7,10,13,16,19 docosahexenoic acid are easily but name as 18: 2 n-6 or 22: 6 n-3 with numeral.For example 20: 5n-3 acid (eicosapentaenoic acid) is represented with first English capitalization EPA of its beginning, and to 22: 6 n-3 acid (docosahexenoic acid) utilize its corresponding D HA to represent, but when the n-3 of same chain length and degree of unsaturation and n-6 acid exist (as 22: 5 acids), then without this kind way.The comparatively general popular name that is used for the acid of n-6 series as shown in the figure.Though will being used for n-3 acid in 18: 4 and eicosapentaenoic acid and docosahexaenoic acid title, parinaric acid (stearidonic acid) title also uses by this way.But only there is n-3 acid in 18: 3 generally to use the popular name alpha-linolenic acid in this n-3 series.Illustrate that linolenic alpha-isomer characterization is more Zao than gamma-Linolenic acid, only relating to linolenic document, particularly early stage document should be mentioned that alpha-acid.
Owing to following two reasons, humans and animals is important to effective absorption of calcium:
1. low calcium absorption and general or excessive UCaE all cause negative calcium balance.
2. normal bone strength needs calcium, and intestinal then can cause the bone fragility to the incomplete absorption of calcium, osteoporosis (a kind of major health).
We had found a kind of by using gamma-Linolenic acid (GLA) or GLA and eicosapentaenoic acid (EPA) compatibility to reduce the way of the new safety of CaE in the past, and this is EP-Al-0, the theme of 517,425 patents.Such just as previously discussed, GLA is linoleic (the main fatty acid in the food) first metabolite, by δ-6-desaturase linoleic acid is converted into GLA.Yet even this conversion also is that speed is restricted slowly in normal health, based on this, it is favourable directly using GLA.
That carries out in the animal and human studies show that: reply though the independent use of GLA and EPA all can cause, GLA and EPA compatibility can obtain optimum efficiency to the excretory reduction of calcium in the urine.
So in the high calcium stone former of 30 recurrences, further the people has been carried out clinical research.When beginning to test, the treatment before all patients have all stopped.Experimental session uses standard calcium food (800mg calcium/sky).After the food sanitation standard food 14 days, the patient is divided into three groups also treated as follows for 12 weeks.
The 1st group: 6g cold water ocean fishes oil every day (FO) (300mg EPA).
The 2nd group: 6g Radix Oenotherae erythrosepalae oil every day (EPO) (540mg GLA).
The 3rd group: the mixture (475 of 6g EPO and FO (80: 20)
mg?GLA，238mg?EPA)。
When stable phase finished in 14 days, carried out calcium 45The baseline values absorption experiment, treated for 12 weeks after, repeat this experiment as stated above, Ga 45The absorption result take passages in down:
Treatment 12 weeks of baseline values
FO 0.36±0.04 0.44±0.06
EPO 0.38±0.03 0.55±0.07
EPO/FO 0.43±0.07 0.68±0.11
Though with the patient of the EPO/FO treatment absorptance EPO height to calcium, the patient who treats with EPO and EPO/FO is to calcium (Ca 45) absorption all increased.
Based on above-mentioned research, one aspect of the present invention is that the metabolite DGLA of GLA and/or its intermediate and generation rapidly is being used for preparing the increase intestinal to the purposes of the medicine of calcium absorption or in the application of raising intestinal to the method for calcium absorption.Because linoleic acid (LA) is the precursor of GLA, so though be that conversion is slow, LA still is certain effect.So the invention still further relates to linoleic purposes,, The present invention be more particularly directed to purposes to the treatment of osteoporosis or other calcium deficiency diseases as below giving proposition.
The present invention also provides raising and the reduction of a kind of promotion to the absorption of calcium to urinate the method that the drainage of calcium is increased system's calcium amount, wherein GLA or the DGLA that uses effective dose every day for the animal or human who suffers from osteoporosis or other calcium deficiency disease or the danger of suffering from this type of disease is arranged with any form easily, or LA.The present invention also provides GLA, DGLA or LA has been used to prepare the purposes of the medicine of use as stated above.
Equally, when preparing medicine with GLA and/or DGLA or carrying out above-mentioned treatment, the present invention then provides the method for the disease of prevention or treatment animal or human's osteoporosis or other symptoms.
As mentioned above, intravital GLA promptly is converted into two height (dihomo)-gamma-Linolenic acid (DGLA); Therefore, DGLA has very similar effects with GLA.
As below will discussing, GLA or DGLA can any suitable form use, as include but not limited to triglyceride, two glyceride ,-glyceride, free fatty, any suitable ester, any suitable salt, comprise that the salt of lithium, sodium, potassium, calcium, zinc, magnesium and other any suitable salt, phospholipid, amide or pharmaceutically acceptable any other form give use.
The preferred dose scope of GLA or DGLA is 0.01-1,000mgkg/ days, more preferably 0.5-50mg/kg/ days, most preferably 2-30mg/kg/ days, can be easily be prepared into medicine by the dosage unit of this dosage (with respect to 70kg's or year people).Because calcium salt is increasing calcium absorption and reducing the excretory while and can replenish calcium, so calcium salt is specially adapted to treat osteoporosis.
GLA or DGLA can use with similar dosage together with any basic fatty acid in n-6 or the n-3 series (as arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid or docosahexenoic acid etc.).Particularly, in view of people's intestinal absorbing state to calcium, preferably with GLA with EPA and/or its metabolite DHA compatibility, this can obtain significant especially effect.
Route of administration suitable ointment oral, parenteral (subcutaneous, intramuscular, intravenous or any other suitable route), enteral, that contain GLA, Emulsion, lotion, use such as patch (patches) part of etc.ing, vagina or rectum all suits.
Can be by as noted above such, use said acid or use these acid by the derivant of equivalence on the such pharmaceutically acceptable and physiology of the GLA that wherein describes in detail and DGLA, as said acid is the derivant of this form, and any acid of being mentioned all can be used as acid wherein.Proved that as effect corresponding effects the path that is applied in this description to be drawn has proved this equivalence with these acid itself or other natural glyceride.The indirect proof of appropriate derivative is that they have the such important result of acid itself in health, concentration in available gas chromatographic analysis blood, body fat or its hetero-organization, with standard technique (as technology that the people introduced such as Pelick, the 23rd page of " Analysis ofLipids and Lipoproteins " Ed Perkins American Oil ChemistsSociety Champaign, Illinois U.S.A) proves this conversion.
Say that briefly suitable situation is that this method is for use chloroform: methanol (2: 1) extraction plasma sample (1ml), extracting solution filters with sodium sulfate, is evaporated to driedly, takes out and put into the 0.5ml chloroform: the first ferment.Separate degrease matter part with thin layer chromatography or silica gel plate, enable to reflect the most delicately that with boron trifluoride-methanol the phospholipid moiety of basic content of fatty acid methylates.Isolate the methyl ester of the fatty acid that obtains, it is carried out Hewlett Packard 5880 gas Chromatographic Determination with six feet the pillar that Chromosorb (Chromosorb) WAW106/230 (on 10%Silar is arranged) is housed.Helium is carrier gas (30ml/ branch).Make oven temperature rise to 190 ℃ with 2 ℃/minute heating rates from 164 ℃.The temperature of detector is 220 ℃, and injector temperature is 200 ℃.Automatically calculate the time of staying and peak area with Hewlett-Packard Level 4 type integrators.Compare by fatty acid methyl ester and to discern the peak with standard.
The present invention relates generally to Therapeutic Method and GLA or DGLA is used for the purposes of pharmaceutical compositions, but what should propose is, required gamma-Linolenic acid and other EFAs of recipe every day can add in edible butter or other food, and when when realizing said purpose, these food will be considered to pharmaceutical composition or (comprise that claim is defined) herein said medicine.
If necessary, can be with such or be used for the present invention with the pharmaceutical composition of the carrier mixing production of pharmaceutically accepting as the natural or synthetic acid of derivant.Yet, be easily providing the GLA of the form of obtainable oil at least at present with high GLA content, therefore mentioned " oil " this term in this manual.
One of present obtainable oil sources is the linoleic acid (its glyceride shape) that oil extract that evening primrose seed oil (as Oenothera biennis. and Oenothera amarckiana) seed of Radix Oenotherae erythrosepalae extracts contains 8%GLA and about 72%, also contains other glyceride (the percentage composition here be that benchmark calculate with total fatty acid) simultaneously.There is the borage kind in other GLA source, and as Borago officinalis, this oil sources that provides is oily abundanter than Oenothera.The member's of Ribes section seed oil also is rich in GLA.Recently by being on the make oil sources to the fungus oil sources that studies show that with the fungus of fermentation culture.Some algae also can produce GLA, can cultivate and collect these algaes.Synthetic also is possible.
Available usual extracting method as cold pressing, screw rod extruding (seed that part was fried) or from seed, extract said oil with methods such as solvent extractions.
The relative scale that is used for the said purpose Radix Oenotherae erythrosepalae oil of this description sample segment (methyl ester form) is listed in the table below:
Cetylate 6.15
Stearate 1.6
Oleate 10.15
Linoleate 72.6
Gamma-Linolenic acid ester 8.9
Above-mentioned seed oil extract can this kind form uses or separablely if required is prepared into a kind of gamma-Linolenic acid and linoleic triglyceride of containing as main fatty acid composition, and gamma-Linolenic acid (if required) accounts for the fluid composition of the overwhelming majority.As if the seed oil extract has stablizes the DGLA effect of (if present).
Available chemosynthesis or the method for fermenting with fungus or Sargassum prepare DGLA.For senior n-6 acid, the natural origin of 22: 4 and n-6 acid in 22: 5 comprises adrenal gland (22: 5) and the kidney (22: 4) that obtains from the slaughterhouse, and these also are the AA source.
N-3 acid is obtained from ocean fishes oil for a long time always, and particularly 20: 5 n-3 (EPA) and 22: 6 n-3 (DHA) acid are all the more so, also ferments from microorganism and Sargassum recently and produces.Available as carry out saponification under the non-oxide condition of gentleness, the gas liquid chromatography of reuse preparation property separates fuel-displaced from above-mentioned oil sources thereafter.Synthetic is difficult, but is not to be impossible, and this method provides another kind of oil sources.
As above summary, said compositions can be easily and the form that is suitable for per os, part, non-intestinal or other administration route administration, suitable medicinal carrier is wherein arranged, this compositions can be mixed with several formulations, therefore, for example, can be mixed with tablet, capsule, absorbable liquid or powder shape preparation when needed, as when gamma-Linolenic acid or other acid can be by skin absorbs, also can be formulated as topical preparation.The said free acid of available protein solubilization is with Radix Oenotherae erythrosepalae (Oenothera) or other oily injectable solutions of preparation hydrolysis.Emulsion agent or salt agent also can be through the transfusion drug administration by injection.
Said preparation also can add antiseptic easily.Have found that concentration is that alpha-tocopherol about 0.1% (weight meter) is suitable for the said purpose of the present invention, and be a kind of stabilizing agent in many possible stabilizing agents well known in the art, said stabilizing agent also comprises as ascorbyl palmitate and stearate.
Certainly, the absolute magnitude that is present in the active substance in any dosage unit is being no more than the amount that is suitable for used injection speed and administering mode, and but then, also wishing also to be enough to obtain needed injection speed under small number of doses.Injection speed depends on desired pharmacological action.
Said compositions also can be foam, Emulsion, suspending agent, vaginal suppository, suppository, cutaneous permeable agent and other suitable dosage forms.
Be for realizing said purpose compositions of the present invention and administration embodiment below.
1. every day, its condition was with the form administration 100-2000mg GLA of soft or hard gelatin capsule or tablet:
A. each capsule 40-80mg GLA (the Radix Oenotherae erythrosepalae oil form).
B. each capsule 50-150mg GLA (borage oil, postfermented tea
Figure C9311832000101
Seed oil, fungal oil or other suitable oil forms).
C. each capsule 100-150mg GLA (triglyceride, or any suitable GLA salt, as lithium, calcium, magnesium, zinc or potassium salt form).
2. administration every day DGLA, dosage is 100-2000mg (above-mentioned 1c form).
3. administration GLA or DGLA (with the EPA compatibility) (have or do not have DHA) give every capsule 10-100mg EPA (cold water ocean fishes oil form) simultaneously as every capsule 40-80mg GLA (Radix Oenotherae erythrosepalae form).
4. administration GLA or DGLA, form of administration be by as above-mentioned 1c in any suitable salt of GLA and excipient (as citric acid-hydrate, sodium bicarbonate or other divalent acid such as tartaric acid or maleic acid) and sweeting agent (as lactose or Sorbitol) and the flavoring agent soluble powder or the effervescent granules agent that make.
5. administration GLA or DGLA, form of administration are liquid Radix Oenotherae erythrosepalae oil, borage or other forms oil itself or the foam or the Emulsion form that prepare with suitable flavour enhancer or stabilizing agent.
6. administration GLA or DGLA, form of administration can be any suitable medicine types with starch, gelatin, He Labai natural gum or other prescription microencapsulations.
7. administration GLA, form of administration is the dosage form of vaginal suppository, suppository, skin plaster agent (Patches) or other any suitable route of administration.
8. calcium-GLA the tablet or the soft or hard gelatin capsule that contain 500mg calcium-GLA salt, 1-5 time/day.

Claims (5)

1.GLA, the application that is used for increasing intestinal calcium absorption medicine in preparation of DGLA or LA itself or its salt or other pharmaceutically acceptable forms and optional EPA, DHA or other basic fatty acids.
2.GLA, DGLA or LA itself or its salt or other pharmaceutically acceptable forms and optional EPA, DHA or other basic fatty acids be used for by exciting calcium absorption to increase and UCaE reduces the application of the medicine that increases system's calcium storage in preparation.
3. according to the purposes of claim 1 or 2, wherein one or more main fatty acids are present in the said medicine with calcium salt forms.
4. according to the purposes of claim 1 or 2, wherein said medicine is that the form with unit dose exists.
5. according to the purposes of claim 3, wherein said medicine is that the form with unit dose exists.
CN93118320A 1992-08-21 1993-08-21 Fatty acid treatment Expired - Fee Related CN1049334C (en)

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GB929217780A GB9217780D0 (en) 1992-08-21 1992-08-21 Fatty acid treatment
GB9217780.7 1992-08-21

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CN1049334C true CN1049334C (en) 2000-02-16

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